Distribution and Detectability of EGFR Exon 20 Insertion Variants in NSCLC

Ou, Sai‐Hong Ignatius; Hong, Jisu; Christopoulos, Petros; Lin, Huamao Mark; Vincent, Sylvie; Churchill, Eric N.; Soeda, Junpei; Kazdal, Daniel; Thomas, Michael

doi:10.1016/j.jtho.2023.01.086

Cited by 28 publications

(11 citation statements)

References 23 publications

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“…Statistics show that there are at least 102 unique ex20ins variants in the US population,withD770_N771insSVD,V769_D770insASV,A763_Y764insFEQA,H773_V774insNPH, and D770_N771insG being the most common variants ( 16 ).The development of novel targeted therapies for NSCLC patients with EGFR ex20 mutations has made remarkable progress in recent years. In 2021, the US Food and Drug Administration (FDA) approved two drugs targeting exon 20 directly: amivantamab and mobocertinib, The CHRYSALYS (NCT02609776) trial, which showed, in previously treated patients harboring exon 20 insertion mutations, a median progression free survival (PFS) of 8.3 months,40% overall response rate, 11.1 months median duration of response, The median overall survival (OS) was 22.8 months.…”

Section: Introductionmentioning

confidence: 99%

Current status and breakthroughs in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations

Hu,

Zhong,

Wang

et al. 2024

Front. Immunol.

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Recently, targeted therapy and immunotherapy have emerged as effective treatment options for non-small cell lung cancer (NSCLC). This progress has been facilitated by the rapid development of diagnostic and therapeutic technologies and the continuous research and development of new drugs, leading to a new era in precision medicine for NSCLC. This is a breakthrough for patients with common mutations in the human epidermal growth factor receptor (EGFR) gene in NSCLC. Consequently, the use of targeted drugs has significantly improved survival. Nevertheless, certain rare genetic mutations are referred to as EGFR exon 20 insertion (ex20ins) mutations, which differ in structure from conventional EGFR gene mutations, namely, exon 19 deletion mutations (19-Del) and exon 21 point mutations. Owing to their distinct structural characteristics, patients harboring these EGFR ex20ins mutations are unresponsive to traditional tyrosine kinase inhibitor (TKI) therapy. This particular group of patients did not fall within the scope of their applicability. However, the activating A763_Y764insFQEA mutation elicits a more pronounced response than mutations in the near and far regions of the C-helix immediately following it and should, therefore, be treated differently. Currently, there is a lack of effective treatments for EGFR ex20ins mutations NSCLC. The efficacy of chemotherapy has been relatively favorable, whereas the effectiveness of immunotherapy remains ambiguous owing to inadequate clinical data. In addition, the efficacy of the first- and second-generation targeted drugs remains limited. However, third-generation and novel targeted drugs have proven to be effective. Although novel EGFR-TKIs are expected to treat EGFR ex20ins mutations in patients with NSCLC, they face many challenges. The main focus of this review is on emerging therapies that target NSCLC with EGFR ex20ins and highlight major ongoing clinical trials while also providing an overview of the associated challenges and research advancements in this area.

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Section: Introductionmentioning

confidence: 99%

Current status and breakthroughs in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations

Hu,

Zhong,

Wang

et al. 2024

Front. Immunol.

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“…Mutations in the EGFR tyrosine kinase domain are drivers of the development of non-small cell lung cancer (NSCLC). Patients with EGFR exon 20 (EGFR Ex20) insertions represent an uncommon subset of approximately 5-12% of EGFR-mutant NSCLC patients [1,2]. Advanced NSCLC with EGFR Ex20 mutations is difficult to treat and is associated with a poor prognosis [3].…”

Section: Introductionmentioning

confidence: 99%

Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis

Illini,

Saalfeld,

Christopoulos

et al. 2024

IJMS

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EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24–45). The response rate in treatment-naïve patients was 27% (95% CI, 8–58). The median progression-free and overall survival was 5 months (95% CI, 3.5–6.5) and 12 months (95% CI, 6.8–17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

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“…Current clinical approaches for detecting indels mainly include first-generation sequencing (FGS, also known as Sanger sequencing), next-generation sequencing (NGS), real-time quantitative polymerase chain reaction (qPCR), and droplet digital PCR (ddPCR) 17 – 19 . However, these methods have their limitations in clinical indel detection.…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, qPCR and ddPCR tests are fast (2 ~ 4 h) and widely used but require costly equipment and cannot easily cover multiple indels in one test. Notably, multiple indel types at a single gene site are common in cancer-related mutations 19 , 22 . For example, more than one hundred c.863_864 4-bp insertions in the NPM1 gene have been reported in AML patients 10 .…”

Section: Introductionmentioning

confidence: 99%

CoHIT: a one-pot ultrasensitive ERA-CRISPR system for detecting multiple same-site indels

Liu,

Wei

et al. 2024

Nat Commun

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Genetic testing is crucial for precision cancer medicine. However, detecting multiple same-site insertions or deletions (indels) is challenging. Here, we introduce CoHIT (Cas12a-based One-for-all High-speed Isothermal Test), a one-pot CRISPR-based assay for indel detection. Leveraging an engineered AsCas12a protein variant with high mismatch tolerance and broad PAM scope, CoHIT can use a single crRNA to detect multiple NPM1 gene c.863_864 4-bp insertions in acute myeloid leukemia (AML). After optimizing multiple parameters, CoHIT achieves a detection limit of 0.01% and rapid results within 30 minutes, without wild-type cross-reactivity. It successfully identifies NPM1 mutations in 30 out of 108 AML patients and demonstrates potential in monitoring minimal residual disease (MRD) through continuous sample analysis from three patients. The CoHIT method is also competent for detecting indels of KIT, BRAF, and EGFR genes. Integration with lateral flow test strips and microfluidic chips highlights CoHIT’s adaptability and multiplexing capability, promising significant advancements in clinical cancer diagnostics.

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Distribution and Detectability of EGFR Exon 20 Insertion Variants in NSCLC

Cited by 28 publications

References 23 publications

Current status and breakthroughs in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations

Current status and breakthroughs in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations

Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis

CoHIT: a one-pot ultrasensitive ERA-CRISPR system for detecting multiple same-site indels

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